A simple and efficient approach for the synthesis of 4-spiro-1,4-DHP derivatives has been developed, involving one-pot three-component reaction of isatins, N,N-dimethylenaminones with ammonium acetate in EtOH–water solution promoted by acetic acid. Compared with the previous [1+2+3]-cyclisation method, this [1+2+1+2]-cyclisation procedure has advantages as it is more environmentally friendly, has easier operational simplicity, and requires milder reaction conditions. Moreover, these novel compounds have been obtained in moderate to good yields and their structures have been confirmed by 1H NMR, 13C NMR and IR and HRMS spectroscopy.